WO2009019119A1 - Sulfanyl derivatives and their use as synthesis intermediates - Google Patents

Sulfanyl derivatives and their use as synthesis intermediates Download PDF

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Publication number
WO2009019119A1
WO2009019119A1 PCT/EP2008/059396 EP2008059396W WO2009019119A1 WO 2009019119 A1 WO2009019119 A1 WO 2009019119A1 EP 2008059396 W EP2008059396 W EP 2008059396W WO 2009019119 A1 WO2009019119 A1 WO 2009019119A1
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WO
WIPO (PCT)
Prior art keywords
mesna
compounds
formula
synthesis intermediates
sulfo
Prior art date
Application number
PCT/EP2008/059396
Other languages
French (fr)
Inventor
Julien Leveque
Nicolas Barbarin
Magali Palacio
Original Assignee
Ucb Pharma S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to PL08775178T priority Critical patent/PL2173708T3/en
Priority to DE602008005459T priority patent/DE602008005459D1/en
Priority to BRPI0814449-4A priority patent/BRPI0814449A2/en
Priority to AT08775178T priority patent/ATE501117T1/en
Application filed by Ucb Pharma S.A. filed Critical Ucb Pharma S.A.
Priority to US12/671,055 priority patent/US8084638B2/en
Priority to EP08775178A priority patent/EP2173708B1/en
Priority to EA201000256A priority patent/EA016532B1/en
Priority to CN2008801018096A priority patent/CN101796023B/en
Priority to CA2695075A priority patent/CA2695075A1/en
Priority to AU2008285765A priority patent/AU2008285765B2/en
Priority to MX2010000826A priority patent/MX2010000826A/en
Priority to JP2010518607A priority patent/JP5264904B2/en
Publication of WO2009019119A1 publication Critical patent/WO2009019119A1/en
Priority to ZA2010/00259A priority patent/ZA201000259B/en
Priority to HK10108328.4A priority patent/HK1141786A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C329/00—Thiocarbonic acids; Halides, esters or anhydrides thereof
    • C07C329/12—Dithiocarbonic acids; Derivatives thereof
    • C07C329/14—Esters of dithiocarbonic acids
    • C07C329/16—Esters of dithiocarbonic acids having sulfur atoms of dithiocarbonic groups bound to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C333/14—Dithiocarbamic acids; Derivatives thereof
    • C07C333/18—Esters of dithiocarbamic acids
    • C07C333/26—Esters of dithiocarbamic acids containing any of the groups, X being a hetero atom, Y being any atom, e.g. N-acyldithiocarbamates

Definitions

  • the present invention relates to new sulfanyl derivatives and to their use as synthesis intermediates, especially for the preparation of pharmaceutically active compounds.
  • 2-mercaptoethanesulfonic acid sodium salt (1 : 1 ) (HS CH2CH2SC>3Na), also known by the generic name of mesna (sodium 2-mercaptoethane sulfonate), has been proven useful as therapeutic agent for the treatment of some diseases; it is known as having mucolytic activity (US Patent 3,576,835); but also as antiviral agent, particularly as an anti-influenza agent (Patent EP 1 596 851 B). Topical use of mesna in surgical procedures that involve the dissection of tissues, is known (Patent
  • the present invention relates to compounds of formula (I), and salts thereof,
  • X is O or N-C(NH)NH 2 ;
  • M + is hydrogen, sodium, disodium, potassium, dipotassium, ammonium (NH4) + , diammonium, quaternary ammonium, calcium or magnesium.
  • M + is hydrogen, sodium or disodium.
  • the compounds of the invention are 2-(2-sulfo-ethylsulfanyl guanidinosulfanyl)-ethanesulfonic acid and salts thereof.
  • the compounds of the invention are also 2-(2-sulfo-ethylsulfanyl carbonylsulfanyl)-ethanesulfonic acid and salts thereof.
  • a preferred compound of the invention is the disodium salt of 2-(2-sulfo- ethylsulfanylguanidinosulfanyl)-ethanesulfonic acid ((C ⁇ H-] -
  • Another preferred compound of the invention is the disodium salt of 2-(2-sulfo- ethylsulfanylcarbonylsulfanyl)-ethanesulfonic acid ((05 ⁇ 84Oz) 2 Na 2 ).
  • Compounds of formula (I) can be in the form of a salt, any pharmaceutically acceptable salt; usually alkaline salt; preferably sodium, disodium, potassium, dipotassium, ammonium (NH4) + , diammonium, quaternary ammonium, calcium, magnesium. More preferably compounds of formula (I) are in the form of disodium salt.
  • Compounds of formula (I) are as follows:
  • Compounds of formula (I) can be in the form of a solvate, which is included in the scope of the present invention.
  • solvates include for example hydrates, alkoxides and the like.
  • Compounds of the invention may be obtained by coupling (ethyl xanthate) O- ethylester carbonodithio acid, potassium salt with (sodium 2 bromoethanesulphonate) 2-bromo-ethanesulfonic acid sodium salt to give ethyl -2-sulfoethylester xanthic acid sodium salt followed by a radical reaction to generate the disodium salt of 2-(2-sulfo- ethylsulfanylcarbonylsulfanyl)-ethanesulfonic acid.
  • guanidine is added in the above reaction medium.
  • the present invention relates to the use of compounds of general formula (I) as synthesis intermediates, especially for the preparation of pharmaceutically active compounds.
  • compounds of formula (I) are used for the synthesis of mesna.
  • Mesna may be obtained by hydrolysis a compound of formula (I), followed by an isolation.
  • the use of compounds of general formula (I) as synthesis intermediates permits to produce mesna with high yield (at least 80 %) and with high purity (at least 85 % , usually more than 90 % and preferably more than 95 %), using a short and simple route and also mainly a safe and economical route.
  • the present invention will be better understood from the following examples which only serve to illustrate the invention. Those skilled in the art will appreciate that routine variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention.
  • EXAMPLES Example 1 Preparation of ethyl -2-sulfoethylester xanthic acid sodium salt.
  • Example 2 Preparation of disodium salt of 2-(2-sulfo-ethylsulfanylcarbonylsulfanyl)- ethanesulfonic acid. Ethyl -2-sulfoethylester xanthic acid sodium salt, as obtained in example 1 ,
  • the compound obtained in example 2 (2g, 5.65mmol) is dissolved in 1 N aqueous sodium hydroxide (20ml, 20mmol) and is stirred at room temperature under a nitrogen atmosphere.
  • the resulting reaction mixture is heated at 8O 0 C for 3 hours. After this time the reaction mixture is allowed to cool before the excess solvent is removed by evaporation under reduced pressure.
  • the resulting white solid is then triturated with ethanol (40ml), under a nitrogen atmosphere, to give a white suspension to which glacial acetic acid (2.4ml) is then added. After stirring for 5 minutes, the suspension is then quickly filtered, washed with ethanol (20ml) and briefly suction- dried. The resulting white solid is then dried in vacuum (4O 0 C) for 30 minutes to give mesna as a white solid, 2.Og, containing only minor impurities by " ⁇ NMR (less than 0.1 %).
  • the starting material ethyl -2-sulfoethylester xanthic acid sodium salt
  • the starting material ethyl -2-sulfoethylester xanthic acid sodium salt
  • thiourea and sulfo-ethyl-thiourea are dangerous synthesis intermediates such as thiourea and sulfo-ethyl-thiourea.
  • the xanthic acid sodium salt, as obtained in example 1 (0.2Og, 0.79mmol) is added to 1 ,2-dichloroethane (5ml) and is heated under reflux (85 0 C). Guanidine (1.25 eq.) is then added. Lauroyl peroxide is then added in portions (8 x 157mg, 0.40mmol) to the reaction mixture over a period of 3 days. Upon cooling the resulting solid is filtered, washed with 1 ,2-dichloroethane, followed by dichloromethane, then air-dried.
  • Example 5 Preparation of mesna from the compound obtained in example 4.
  • the compound obtained in example 4 is re crystallized according to the process described in example 2.
  • the obtained compound leads to mesna by following the process of preparation described in example 3.

Abstract

The present application relates to sulfanyl derivatives of formula (I) and to their use as synthesis intermediates, especially for the preparation of the pharmaceutically active compound mesna. Formula (I), wherein X is O or N-C(NH)NH2; M + is hydrogen, sodium, disodium, potassium, dipotassium, ammonium (NH4)+, diammonium, quaternary ammonium, calcium or magnesium.

Description

SULFANYL DERIVATIVES AND THEIR USE AS SYNTHESIS INTERMEDIATES
The present invention relates to new sulfanyl derivatives and to their use as synthesis intermediates, especially for the preparation of pharmaceutically active compounds. 2-mercaptoethanesulfonic acid sodium salt (1 : 1 ) (HS CH2CH2SC>3Na), also known by the generic name of mesna (sodium 2-mercaptoethane sulfonate), has been proven useful as therapeutic agent for the treatment of some diseases; it is known as having mucolytic activity (US Patent 3,576,835); but also as antiviral agent, particularly as an anti-influenza agent (Patent EP 1 596 851 B). Topical use of mesna in surgical procedures that involve the dissection of tissues, is known (Patent
EPO 930 878 B). Mesna protects the urinary tract from urotoxic symptoms in the treatment of tumour disease with ifosfamide (US Patent 6,322,812).
We have now found an alternative process for preparing mesna.
We have now found an improved process for preparing mesna, using a safe and economical route.
In a first aspect, the present invention relates to compounds of formula (I), and salts thereof,
Figure imgf000002_0001
(I) wherein
X is O or N-C(NH)NH2;
M + is hydrogen, sodium, disodium, potassium, dipotassium, ammonium (NH4)+, diammonium, quaternary ammonium, calcium or magnesium.
Usually M + is hydrogen, sodium or disodium. Usually the compounds of the invention are 2-(2-sulfo-ethylsulfanyl guanidinosulfanyl)-ethanesulfonic acid and salts thereof. Usually the compounds of the invention are also 2-(2-sulfo-ethylsulfanyl carbonylsulfanyl)-ethanesulfonic acid and salts thereof.
A preferred compound of the invention is the disodium salt of 2-(2-sulfo- ethylsulfanylguanidinosulfanyl)-ethanesulfonic acid ((CβH-] -| ^54Os)2Na2).
Another preferred compound of the invention is the disodium salt of 2-(2-sulfo- ethylsulfanylcarbonylsulfanyl)-ethanesulfonic acid ((05^84Oz)2Na2).
Compounds of formula (I) can be in the form of a salt, any pharmaceutically acceptable salt; usually alkaline salt; preferably sodium, disodium, potassium, dipotassium, ammonium (NH4)+, diammonium, quaternary ammonium, calcium, magnesium. More preferably compounds of formula (I) are in the form of disodium salt. Compounds of formula (I) are as follows:
Figure imgf000003_0001
Figure imgf000003_0002
Compounds of formula (I) can be in the form of a solvate, which is included in the scope of the present invention. Such solvates include for example hydrates, alkoxides and the like.
Compounds of formula (I) are very stable and can be used as synthesis intermediates. In particular hydrolysis of the compounds of the invention gives mesna and dimesna.
Compounds of the invention may be obtained by coupling (ethyl xanthate) O- ethylester carbonodithio acid, potassium salt with (sodium 2 bromoethanesulphonate) 2-bromo-ethanesulfonic acid sodium salt to give ethyl -2-sulfoethylester xanthic acid sodium salt followed by a radical reaction to generate the disodium salt of 2-(2-sulfo- ethylsulfanylcarbonylsulfanyl)-ethanesulfonic acid. To obtain the disodium salt of 2-(2- sulfo-ethylsulfanylguanidinosulfanyl)-ethanesulfonic acid, guanidine is added in the above reaction medium.
In another aspect, the present invention relates to the use of compounds of general formula (I) as synthesis intermediates, especially for the preparation of pharmaceutically active compounds.
According to a first embodiment, compounds of formula (I) are used for the synthesis of mesna.
Mesna may be obtained by hydrolysis a compound of formula (I), followed by an isolation. The use of compounds of general formula (I) as synthesis intermediates permits to produce mesna with high yield (at least 80 %) and with high purity (at least 85 % , usually more than 90 % and preferably more than 95 %), using a short and simple route and also mainly a safe and economical route. The present invention will be better understood from the following examples which only serve to illustrate the invention. Those skilled in the art will appreciate that routine variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention. EXAMPLES Example 1 : Preparation of ethyl -2-sulfoethylester xanthic acid sodium salt.
Potassium O-ethylxanthate (3 x 95mg, O.δOmmol) is added portion wise every 1 .5 hours to a solution of sodium 2-bromoethanesulphonate (0.42g, 2.00mmol) in acetonitrile (15ml). The reaction mixture is heated at 850C, under a nitrogen atmosphere, for a total of 6 hours. Upon cooling the suspension is filtered, washed with acetonitrile and air-dried affording an off-white solid.
1 H NMR (DMSO d6) δ (ppm) 4.67 (q, 2H), 3.40 (2H, m), 3.26 (m, 2H), 1 .39 (t, 3H).
Example 2: Preparation of disodium salt of 2-(2-sulfo-ethylsulfanylcarbonylsulfanyl)- ethanesulfonic acid. Ethyl -2-sulfoethylester xanthic acid sodium salt, as obtained in example 1 ,
(0.2Og, 0.79mmol) is added to 1 ,2-dichloroethane (5ml) and is heated under reflux (850C). Lauroyl peroxide is then added in portions (8 x 157mg, 0.40mmol) to the reaction mixture over a period of 3 days. Upon cooling the resulting solid is filtered, washed with 1 ,2-dichloroethane, followed by dichloromethane, then air-dried. The solid above mentioned (100mg, 0.28mmol) is suspended in ethanol (5ml) and heated under gentle reflux (compound stable by "Η NMR analysis). Water (~0.5ml) is then added to give complete solution, and reflux is continued for 2h (compound stable by "Η NMR analysis). The solution is allowed to cool overnight to give a suspension which is filtered. The white solid is washed with cold ethanol (1 ml_) and suction-dried to give the purified compound, 75mg (75% recovery). The compound is pure by "Η NMR analysis. Melting point : 284.8°C.
1H NMR (DMSO d6) δ (ppm) 3.26 (4H, m), 3.08 (4H, m) 13C NMR (DMSO d6) δ (ppm) 51.4, 26.8 Example 3: Preparation of mesna from the compound obtained in example 2.
The compound obtained in example 2 (2g, 5.65mmol) is dissolved in 1 N aqueous sodium hydroxide (20ml, 20mmol) and is stirred at room temperature under a nitrogen atmosphere. The resulting reaction mixture is heated at 8O0C for 3 hours. After this time the reaction mixture is allowed to cool before the excess solvent is removed by evaporation under reduced pressure. The resulting white solid is then triturated with ethanol (40ml), under a nitrogen atmosphere, to give a white suspension to which glacial acetic acid (2.4ml) is then added. After stirring for 5 minutes, the suspension is then quickly filtered, washed with ethanol (20ml) and briefly suction- dried. The resulting white solid is then dried in vacuum (4O0C) for 30 minutes to give mesna as a white solid, 2.Og, containing only minor impurities by "Η NMR (less than 0.1 %).
This process leads to an active ingredient, mesna, of high purity profile. The starting material (ethyl -2-sulfoethylester xanthic acid sodium salt) is safe and easy to use. In fact its use does not require specific precautions, as it is not an explosive compound. Mainly this process allows to avoid using dangerous synthesis intermediates such as thiourea and sulfo-ethyl-thiourea.
1 H NMR (DMSO d6) δ (ppm) 3.26 (4H, m), 3.08 (4H, m). Example 4: Preparation of disodium salt of 2-(2-sulfo-ethylsulfanylguanidinosulfanyl)- ethanesulfonic acid.
The xanthic acid sodium salt, as obtained in example 1 , (0.2Og, 0.79mmol) is added to 1 ,2-dichloroethane (5ml) and is heated under reflux (850C). Guanidine (1.25 eq.) is then added. Lauroyl peroxide is then added in portions (8 x 157mg, 0.40mmol) to the reaction mixture over a period of 3 days. Upon cooling the resulting solid is filtered, washed with 1 ,2-dichloroethane, followed by dichloromethane, then air-dried. Example 5: Preparation of mesna from the compound obtained in example 4.
The compound obtained in example 4 is re crystallized according to the process described in example 2. The obtained compound leads to mesna by following the process of preparation described in example 3.

Claims

1. Compounds of formula (I), and salts thereof,
Figure imgf000006_0001
(I) wherein X is O or N-C(NH)NH2;
M + is hydrogen, sodium, disodium, potassium, dipotassium, ammonium (NH4)+, diammonium, quaternary ammonium, calcium or magnesium.
2. A compound according to claim 1 wherein X is N-C(NH)NH2.
3. A compound according to claim 1 wherein X is O.
4. A compound according to claim 1 or 2 wherein it is the disodium salt of 2-(2- sulfo-ethylsulfanylguanidinosulfanyl)-ethanesulfonic acid.
5. A compound according to claim 1 or 3 wherein it is the disodium salt of 2-(2- sulfo-ethylsulfanylcarbonylsulfanylj-ethanesulfonic acid.
PCT/EP2008/059396 2007-08-03 2008-07-17 Sulfanyl derivatives and their use as synthesis intermediates WO2009019119A1 (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
EP08775178A EP2173708B1 (en) 2007-08-03 2008-07-17 Sulfanyl derivatives and their use as synthesis intermediates
BRPI0814449-4A BRPI0814449A2 (en) 2007-08-03 2008-07-17 Compounds and salts thereof
AT08775178T ATE501117T1 (en) 2007-08-03 2008-07-17 SULFANYL DERIVATIVES AND THEIR USE AS SYNTHETIC INTERMEDIATE PRODUCTS
CN2008801018096A CN101796023B (en) 2007-08-03 2008-07-17 Sulfanyl derivatives and their use as synthesis intermediates
US12/671,055 US8084638B2 (en) 2007-08-03 2008-07-17 Sulfanyl derivatives and their use as synthesis intermediates
DE602008005459T DE602008005459D1 (en) 2007-08-03 2008-07-17 Sulphany derivatives and their use as synthetic intermediates
EA201000256A EA016532B1 (en) 2007-08-03 2008-07-17 Sulfanyl derivatives and their use as synthesis intermediates
PL08775178T PL2173708T3 (en) 2007-08-03 2008-07-17 Sulfanyl derivatives and their use as synthesis intermediates
CA2695075A CA2695075A1 (en) 2007-08-03 2008-07-17 Sulfanyl derivatives and their use as synthesis intermediates
AU2008285765A AU2008285765B2 (en) 2007-08-03 2008-07-17 Sulfanyl derivatives and their use as synthesis intermediates
MX2010000826A MX2010000826A (en) 2007-08-03 2008-07-17 Sulfanyl derivatives and their use as synthesis intermediates.
JP2010518607A JP5264904B2 (en) 2007-08-03 2008-07-17 Sulfanyl derivatives and their use as synthetic intermediates
ZA2010/00259A ZA201000259B (en) 2007-08-03 2010-01-13 Sulfanyl derivatives and their use as synthesis intermediates
HK10108328.4A HK1141786A1 (en) 2007-08-03 2010-09-02 Sulfanyl derivatives and their use as synthesis intermediates

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP07015316.8 2007-08-03
EP07015316 2007-08-03
EP07019390 2007-10-03
EP07019390.9 2007-10-03

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AT (1) ATE501117T1 (en)
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BR112017004533A2 (en) * 2014-09-08 2018-05-08 Gotham Biopharmaceuticals Inc method for treating pulmonary sarcoidosis
US10158458B2 (en) * 2015-05-29 2018-12-18 Huawei Technologies Co., Ltd. Systems and methods for partial collision multiple access

Citations (4)

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US2695310A (en) * 1951-12-12 1954-11-23 Lever Brothers Ltd Preparation of guanidinium mercaptoalkanesulfonate
WO1998014426A1 (en) * 1996-10-01 1998-04-09 Bionumerik Pharmaceuticals, Inc. Process for producing mercaptoalkanesulfonates and phosphonates and derivatives thereof
WO2002006216A1 (en) * 2000-07-18 2002-01-24 Bionumerik Pharmaceuticals, Inc. Method for preparing disodium 2.2'-dithiobis(ethanesulphonate)
WO2005058005A2 (en) * 2003-12-17 2005-06-30 Bionumerik Pharmaceuticals, Inc. Process for synthesizing disulfides

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JPS59231064A (en) * 1983-06-13 1984-12-25 Mitsui Toatsu Chem Inc Preparation of 2-mercaptoethylamine compound
JP2881033B2 (en) * 1991-02-05 1999-04-12 三井化学株式会社 Method for producing mercaptoamines

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US2695310A (en) * 1951-12-12 1954-11-23 Lever Brothers Ltd Preparation of guanidinium mercaptoalkanesulfonate
WO1998014426A1 (en) * 1996-10-01 1998-04-09 Bionumerik Pharmaceuticals, Inc. Process for producing mercaptoalkanesulfonates and phosphonates and derivatives thereof
WO2002006216A1 (en) * 2000-07-18 2002-01-24 Bionumerik Pharmaceuticals, Inc. Method for preparing disodium 2.2'-dithiobis(ethanesulphonate)
WO2005058005A2 (en) * 2003-12-17 2005-06-30 Bionumerik Pharmaceuticals, Inc. Process for synthesizing disulfides

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SCHRAMM, C.H. ET AL.: "The synthesis of mercaptoalkanesulfonic acids", J. AM. CHEM. SOC., vol. 77, no. 23, 1955, pages 6231 - 6233, XP002467264 *

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EP2173708B1 (en) 2011-03-09
US20100292505A1 (en) 2010-11-18
CA2695075A1 (en) 2009-02-12
CN101796023B (en) 2012-06-27
MX2010000826A (en) 2010-03-01
ZA201000259B (en) 2011-03-30
EA016532B1 (en) 2012-05-30
AU2008285765A1 (en) 2009-02-12
HK1141786A1 (en) 2010-11-19
JP2010535168A (en) 2010-11-18
JP5264904B2 (en) 2013-08-14
CN101796023A (en) 2010-08-04
BRPI0814449A2 (en) 2015-08-25
DE602008005459D1 (en) 2011-04-21
EA201000256A1 (en) 2010-08-30
AU2008285765B2 (en) 2011-02-03
KR20100043220A (en) 2010-04-28
ATE501117T1 (en) 2011-03-15
US8084638B2 (en) 2011-12-27
EP2173708A1 (en) 2010-04-14
PL2173708T3 (en) 2011-08-31

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